US 201403 15928A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0315928A1 DarOut et al. (43) Pub. Date: Oct. 23, 2014 (54) SUBSTITUTEDAMIDE COMPOUNDS Publication Classification (71) Applicant: Pfizer Inc., New York, NY (US) (51) Int. Cl. C07D40 L/4 (2006.01) (72) Inventors: Etzer Darout, Cambridge, MA (US); A 6LX3/59 (2006.01) Robert Dullea, Groton, MA (US); Julie A6II 45/06 (2006.01) Jia Li Hawkins, Weston, CT (US); C07D 413/4 (2006.01) Allyn T. Londregan, Barrington, RI A613 L/437 (2006.01) (US); Paula M. Loria, Killingworth, CT A 6LX3L/24709 (2006.01) (US); Bruce Maguire, Chester, CT A613 L/4545 (2006.01) (US); Kim F. McClure, Mystic, CT C07D 487/04 (2006.01) (US); Donna N. Petersen, Salem, CT C07D 47L/04 (2006.01) (52) U.S. Cl. (US); David W. Piotrowski, Waterford, CPC ............ C07D401/14 (2013.01); C07D487/04 CT (US) (2013.01); A61 K3I/519 (2013.01); A61 K 45/06 (2013.01); C07D 471/04 (2013.01); (73) Assignee: Pfizer Inc., New York, NY (US) A6 IK3I/437 (2013.01); A61 K3I/4709 (2013.01); A61 K3I/4545 (2013.01); C07D 413/14 (2013.01) (21) Appl. No.: 14/253,084 USPC ........ 514/259.3:544/281: 546/117: 514/300; 546/143: 514/310:546/194; 514/318; 546/113 (22) Filed: Apr. 15, 2014 (57) ABSTRACT The present invention is directed at substituted amide com pounds, pharmaceutical compositions containing Such com Related U.S. Application Data pounds and the use of such compounds to reduce plasma lipid (60) Provisional application No. 61/812,864, filed on Apr. levels. Such as LDL-cholesterol and triglycerides and accord 17, 2013, provisional application No. 61/880,336, ingly to treat diseases which are exacerbated by high levels of filed on Sep. 20, 2013, provisional application No. LDL-cholesterol and triglycerides, such as atherosclerosis 61/898,667, filed on Nov. 1, 2013. and cardiovascular diseases, in mammals, including humans. Patent Application Publication Oct. 23, 2014 Sheet 1 of 10 US 2014/0315928A1 mixSN sawmar &N - frr as a was a SunOO) Patent Application Publication Oct. 23, 2014 Sheet 2 of 10 US 2014/0315928A1 15 Sa , S. - 8 - -- N rmera...a...a...ac. r ear {3 . D -P--- . c. 2ss: CN a -------- e -er--- --- - wer & tri-preppy-per-Trrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrl. c. c s c C C s d s d s r cy w (Sino) u" Patent Application Publication Oct. 23, 2014 Sheet 3 of 10 US 2014/0315928A1 3. s C C al d s Y CN (SunO) u" Patent Application Publication Oct. 23, 2014 Sheet 4 of 10 US 2014/0315928A1 ·{}{}{}A oooº ·{}{}{}{} door *oooº ºoooº |000?. (Suo) u Patent Application Publication Oct. 23, 2014 Sheet 5 of 10 US 2014/0315928A1 Patent Application Publication Oct. 23, 2014 Sheet 6 of 10 US 2014/0315928A1 (SLOC) u Patent Application Publication Oct. 23, 2014 Sheet 7 of 10 US 2014/0315928A1 Patent Application Publication Oct. 23, 2014 Sheet 8 of 10 US 2014/0315928A1 Patent Application Publication Oct. 23, 2014 Sheet 9 of 10 US 2014/0315928A1 {000'09 ?000’07 #000’o, Patent Application Publication Oct. 23, 2014 Sheet 10 of 10 US 2014/0315928A1 aaraaaaarara -----------Mr. ----- - referre --- reyers for first rrrr.Trri rty-fir r ---- (SunOO) u US 2014/03 15928A1 Oct. 23, 2014 SUBSTITUTEDAMIDE COMPOUNDS SUMMARY OF THE INVENTION CROSS-REFERENCE TO RELATED 0006. The present invention is directed to compounds of Formula I APPLICATION 0001. This application claims the benefit of priority of U.S. provisional Patent Application Ser. No. 61/812,864, Formula I filed Apr. 17, 2013: U.S. provisional Patent Application Ser. RI No. 61/880,336, filed Sep. 20, 2013 and U.S. provisional lo Patent Application Ser. No. 61/898,667 filed Nov. 1, 2013, HN1 No.1 which are incorporated herein by reference in their entirety for all purposes. N- als, BACKGROUND OF INVENTION R?-- || 0002 The present invention relates to substituted amide N compounds, pharmaceutical compositions containing Such R3 compounds and the use of Such compounds to treat cardio vascular disease including atherosclerosis, hyperlipidemia, or a pharmaceutically acceptable salt thereof wherein hypercholesterolemia, and hypertriglyceridemia in mam R" is pyrid-2-yl, isoquinolin-1-yl or 1H-pyrrolo[2.3-clpyri mals, including humans. din-7-yl; 0003 Atherosclerosis, a disease of the arteries, is recog R" is optionally mono- or di-substituted with chloro or (C- nized to be the leading cause of death in the United States and C.)alkyl: Western Europe. The pathological sequence leading to ath X and Y are independently either N or C(H), provided that at erosclerosis and occlusive heart disease is well known. The least one of X or Y is C(H): earliest stage in this sequence is the formation of “fatty R’ is H. fluoro, hydroxyl or methyl: streaks' in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence R is of lipid deposits found principally within Smooth-muscle cells and in macrophages of the intima layer of the arteries 0007 and aorta. Further, it is postulated that most of the cholesterol found within the fatty streaks, in turn, gives rise to develop ment of the “fibrous plaque,” which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin and proteoglycans. These cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the “complicated lesion, which accounts for the arterial occlusion and tendency toward mural R O thrombosis and arterial muscle spasm that characterize N advanced atherosclerosis. NNN R7 0004 Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovas Yo cular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed wherein Rand Rare each independently H. methyl, halo or emphasis on lowering plasma cholesterol levels, and low (C-C)alkyloxy, provided that only one of RandR is halo; density lipoprotein cholesterol in particular, as an essential wherein R'' and R'' are each independently H, (C-C)alkyl step in prevention of CVD. The upper limits of “normal are or (C-C)cycloalkyl, and now known to be significantly lower than heretofore appre wherein R is hydroxyl, (C-C)alkyloxy, (C-C)alkoxycar ciated. As a result, large segments of Western populations are bonyloxy(C-C)alkyloxy, or (C-C)alkylcarbonyloxy(C- now realized to be at particularly high risk. Additional inde C.)alkoxy. pendent risk factors include glucose intolerance, left ven 0008. The present application is also directed to methods tricular hypertrophy, hypertension, and being of the male sex. for treating dyslipidemia, hypercholesterolemia (including Cardiovascular disease is especially prevalent among dia heterozygous and homozygous familial hypercholester betic Subjects, at least in part because of the existence of olemia), hypertriglyceridemia, hyperlipidemia, hypoalphali multiple independent risk factors in this population. Success poproteinemia, metabolic syndrome, diabetic complications, ful treatment of hyperlipidemia in the general population, and atherosclerosis, stroke, Vascular dimensia, chronic kidney in diabetic subjects in particular, is therefore of exceptional disease, coronary heart disease, coronary artery disease, ret medical importance. inopathy, inflammation, thrombosis, peripheral vascular dis 0005 While there are a variety of anti-atherosclerosis ease or congestive heart failure in a mammal by administering compounds, cardiovascular disease is still a leading cause of to a mammal in need of Such treatment a therapeutically death and accordingly, there is a continuing need and a con effective amount of a compound of Formula I or a pharma tinuing search in this field of art for alternative therapies. ceutically acceptable salt of said compound. US 2014/03 15928A1 Oct. 23, 2014 0009. The present application also is directed to pharma R is ceutical compositions which comprise a therapeutically effective amount of a compound of Formula I, or a pharma 0017 ceutically acceptable salt of said compound and a pharma ceutically acceptable carrier, vehicle or diluent. 0010. In addition, the present application is directed to R8 N 4. pharmaceutical combination compositions comprising: a N n N therapeutically effective amount of a composition comprising 21 C s /N 0.011 a first compound, said first compound being a com N N/ R6 2N. pound of Formula I or a pharmaceutically acceptable salt of said compound; 0012 a second compound, said second compound being a R O R NN-" lipid modulating agent; and N Y (/ 0013 a pharmaceutically acceptable carrier, vehicle or R7 NNN 2N diluent. Yo 0014 Examples of lipid modulating agents include a R 14 lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG CoA synthase inhibitor, an HMG-CoA reductase gene R O expression inhibitor, an HMG-CoA synthase gene expression s N st inhibitor, an MTP/Apo B secretion inhibitor, a CETP inhibi ( -N NNN) {N-O tor, a bile acid absorption inhibitor, a cholesterol absorption V inhibitor, a cholesterol synthesis inhibitor, a squalene Syn R10 thetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a combined squalene epoxidase/squalene cyclase inhibitor, a fibrate, niacin, a combination of niacin R N O and lovastatin, an ion-exchange resin, an antioxidant, an R15 ACAT inhibitor and a bile acid sequestrant. NNN N1 V Y. 0015. Another aspect of this invention is directed to a R10 method of treating dyslipidemia by administering to a patient in need thereof a therapeutically effective amount of a com wherein RandR are each independently H, methyl, halo or pound that selectively inhibits the translation of PCSK9 (C-C)alkyloxy, provided that only one of RandR is halo; mRNA to PCSK9 protein.